Compositions and methods for prophylaxis and therapy for meniere&#39;s disease

ABSTRACT

Provided are articles of manufacture, compositions and methods for prophylaxis and/or therapy for disorders involving dizziness and/or vertigo. The articles of manufacture and compositions contain lamotrigen and/or bupropion. The compositions include pharmaceutical compositions which are intended to alleviate dizziness and/or vertigo. In certain aspects the disclosure includes articles of manufacture and kits which include printed material which provides an indication that the articles or compositions are intended to be used for prophylaxis and/or therapy of Meniere&#39;s Disease or a symptom thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/808,223, filed Nov. 9, 2017, which is a continuation of U.S.application Ser. No. 14/730,740, filed Jun. 4, 2015, now U.S. Pat. No.9,814,723, which is a continuation-in-part of U.S. application Ser. No.14/183,148, filed Feb. 18, 2014, now abandoned, which claims priority toU.S. application No. 61/768,414, filed Feb. 23, 2013, the disclosures ofeach of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to compositions and methods forprophylaxis and therapy of several types of dizziness.

BACKGROUND OF THE INVENTION

Dizziness and imbalance problems affect more than 90 million Americansand are one of the most common complaints in clinic patients. Thesesymptoms can be caused by a range of vestibular and neurologicaldisorders, but almost two-thirds of dizziness cases are a result ofMeniere's disease, migraine-associated vertigo (MAV), and phobicpostural vertigo/chronic subjective dizziness (PPV/CSD). The etiology ofall these disorders is still unclear and successful pharmaceuticaltreatments are lacking.

Meniere's Disease

In 1861 Prosper Meniere first published an article describing an innerear disorder that caused vertigo and hearing loss.^(i) Today thedisorder, known as Meniere's disease (MD) affects 20 to 200 per 100,000individuals with men and women (typically between 30-50 years old) beingaffected almost equally.^(ii) Meniere's disease continues to becharacterized by the same symptoms described in 1861. The AmericanAcademy of Otolaryngology—Head and Neck Surgery (AAO-HNS) criteria fordiagnosis includes recurrent spontaneous and episodic vertigo (vertigothat is debilitating and usually causes nausea or vomiting without lossof consciousness) that lasts at least 20 minutes and up to several dayswith hearing loss, aural fullness and/or tinnitus.^(iii) This vestibulardisorder has several proposed causes, but is truly idiopathic due toinconsistent symptoms without explanations. It is commonly thought thatendolymphatic hydrops causes Meniere's disease.^(iv) Hydrops form eitherbecause a blockage prevents the endolymphatic fluid from being properlyabsorbed or because there is an excess in endolymphatic fluidproduction. The resulting increase in inner ear pressure is proposed tothen cause vertigo attacks and the aural fullness sensationcharacteristic of Meniere's disease.^(v) However, hydrops may be anepiphenomenon rather than the primary cause because it is not found inevery Meniere's patient. Additionally, one study has discovered thatanimal models do not present differences in hydrostatic pressures in theperilymph and endolymph despite the presence of significanthydrops.^(vi) Other underlying causes of Meniere's disease have beenresearched, like spreading depression and characteristically similarmigraines.

Migraine has been frequently associated with Meniere's disease and thetwo disorders share several likenesses. A study on the comorbidity ofmigraine and Meniere's disease found a significantly higher lifetimeprevalence of migraine in the MD group compared to an age- andsex-matched control group: 44 out of 78 patients with MD (56%) had ahistory of migraine compared to 20 out of 78 in the control group (25%)for both men and women.^(vii) The same study found that 35 (45%)patients reported Meniere's attacks were always accompanied by at leastone migrainous symptom (migrainous headaches, photophobia, or auralsymptoms) and 9 (11%) patients reported Meniere attacks were sometimesaccompanied by migrainous symptoms. In our own research on dizziness andbalance disorders between 2011 and 2012 we found that 90 patients werediagnosed with Meniere's disease and of these patients 13 (14%)individuals were diagnosed with migraine and 10 (11%) individuals werediagnosed with anxiety and migraine, composing a total of 23 (25%)patients who were diagnosed with some form of migraine. Both vestibulardisorders have a similar non-drug treatment as well, including avoidanceof caffeine, chocolate, alcohol, tobacco and salt.^(viii) Additionally,Meniere's disease and migraines both have significant genetic componentsand it is possible that patients are inheriting ion channelabnormalities shared by the brain and inner ear that causes bothdisorders.^(ix) It has not been definitively determined whether migrainemimics Meniere's disease or causes it, but the several commonalitiessuggest that MD patients with migraine may find relief withantimigrainous medication.

Anxiety is another diagnosis frequently seen with Meniere's disease(MD). Many MD patients become anxious, depressed or stressed due to thesevere repeated vertigo. This anxiety can even develop into a secondaryvestibular disorder: phobic postural vertigo (or chronic subjectivedizziness if symptoms persist for more than 3 months). A study assessedMD patients using the Dutch Daily Hassles List, Coping Inventory forStressful Situations (CISS), Symptoms Checklist 90 (SCL-90), NEO FiveFactor Inventory (NEO-FFI), General Health Questionnaire (GHQ-12), andthe Short Form Health Survey 36 (SF-36).^(x) The results showed thatMeniere's disease patients did not have any abnormalities inpersonality, but had more daily stressors, had a worse quality of lifeand more instances of anxiety and depression compared to a healthycontrol group. These psychological difficulties were more profound inpatients who had been living with Meniere's disease for a longer timeand in those who experienced more frequent symptoms. Another study foundthat more than half of the 800 Meniere's patients enrolled reportedexperiencing partial or full posttraumatic stress disordersymptoms.^(xi) Our own preliminary analysis revealed a similar patternof anxiety comorbidities with, again 10 (11%) of 90 MD patientsdiagnosed with both anxiety and migraine and 26 (29%) patients diagnosedwith only anxiety. These numbers combined with migraine prevalencetotaled to slightly more than half (54%) of our total MD sample with ananxiety and/or migraine comorbidity. However, most treatments forMeniere's disease do not address migraine or anxiety symptoms.

In addition to the aforementioned lifestyle and diet changes, Meniere'sdisease can be treated in a variety of ways, all of which are short ofbeing complete successes for one reason or another. Streptomycintherapy, while effective in vertigo control, after repeated treatmentshas an ototoxic effect and must be stopped if the patient experiences arapid decline in vestibular function, develops hearing loss or manifestsoscillopsia.^(xii) Intratympanic gentamicin also has a high rate ofsensorineural hearing loss.^(xiii) The efficacy of invasive surgery isquestionable as well. A study conducting both endolymphatic sacsurgeries and mastoidectomies indicated that the benefits ofendolymphatic sac surgery may be a surgical placebo effect.^(xiv)Patients who undergo vestibular neurectomies rarely have a reoccurrenceof vertigo and have no risk of hearing loss. Despite these positiveresults, the procedure is very stressful and older patients areineligible because of the greater difficulty to compensate for lostvestibular function. Irrefutably the treatment with the least sideeffects is the Meniett device, but many patients cannot afford thedevice priced around $3,500 because of reluctant insurers. A lot ofpharmacotherapy research has been conducted too; however, few haveadvanced to clinical usage. Most studies, such as those on the effectsof betahistine, do not meet high methodological standards and theevidence is deemed inconclusive.^(xv) Most importantly, the majority ofthese treatments are merely symptomatic and an effective prophylacticintervention has not yet been developed.

Migraine-Associated Vertigo (MAV)

Beyond the many commonalities shared between migraines and Meniere'sdisease, migraines also have their own frequent comorbidity with vertigoand dizziness. In a study conducted by Kayan and Hood, motion sicknesswas reported by over half of the participants diagnosed withmigraine.^(xvi) Another study revealed 3.2% comorbidity between migraineand vertigo in the general population despite an expected overlap ofonly 1.1% by chance alone.^(xvii) Researchers reasoned that thisincreased prevalence could be due to a higher occurrence of dizzinessand vertigo symptoms in migraine patients than in controls, but alsocould be caused by the recent recognition of migraine-associated vertigo(MAV) as its own vestibular disorder. The details of migraine-associatedvertigo regarding terminology, causation, criteria, and treatment arestill highly debated. However, Neuhauser et al.'s criteria have beencommonly used to diagnosis patients.^(xviii) Definitemigraine-associated vertigo is based on the patient having episodicvestibular symptoms of at least moderate severity (rotational vertigo,other illusory self or object motion, positional vertigo or head motionintolerance), migraine according to the International Headache Society(IHS) criteria, at least one migrainous symptom during at least twovertiginous attacks (migrainous headache, photophobia, phonophobia, orvisual or other auras), and all other causes ruled out by appropriateinvestigations. A probable diagnosis of migraine-associated vertigo isbased on episodic vestibular symptoms of at least moderate severity; atleast one migraine according to the IHS criteria, migrainous symptomsduring vertigo, migraine-specific precipitants of vertigo (specificfoods, sleep irregularities, hormonal changes), or response toanti-migraine drugs; and all other causes ruled out by appropriateinvestigations. There are more women than men with symptoms of migraine;in the United States rates range from 16-18% for women and 5-6% formen.^(xix) Although general population prevalence rates have not beencalculated, if sample study statistics are reflective of the populationit would be expected that 4.5% of women and 1.5% of men in the U.S.experience migraine associated vertigo. Yet, because the exactmechanisms of this disorder are still debated, effective prophylactictreatment that could greatly improve the quality of life for theseindividuals has not been implemented.

Most MAV patients are given medications that will only abort symptomaticvertigo and migraine attacks once they are already occurring. Thesemedications include benzodiazepines (Valium), cyproheptadine, ergots,methysergide, non-steroidal anti-inflammatory drugs (Ibuprofen), opiatesor triptans (Maxalt, Relpax).^(xx) Nonpharmacologic remedies includebutterbur root extract, dietary restrictions (caffeine), foodsupplements, magnesium, and better sleep hygiene. Common prophylactictreatments for migraine such as beta-blockers, calcium antagonists,anticonvulsants (topiramate or depakote) and antidepressants arefrequently being used in MAV cases, although it is still debated whetherthese medications have a positive effect on both migraine and vertigoaspects of MAV. All of these treatment options lack a high-level ofevidence and randomized controlled study designs. Further complicatingefficient treatment for MAV patients is anxiety comorbidity andanxiety-related dizziness (PPV). It is well recognized that migrainecommonly occurs with symptoms of depression and anxiety. For instance,the life time prevalence of panic disorder is 16% in patients withmigraine compared with 4% in control groups.^(xxi) Eckhardt-Henn et al.concluded that migraine-associated vertigo and Meniere's disease seem tobe the vestibular disorders with the highest risk of secondary anxietysymptoms.^(xxii) An approach that embraces both prophylactic MAVtreatment and anti-anxiety medication will provide patients with themost relief, but such an approach has not previously been available. Thepresent invention meets these and other needs related to prophylaxis andtherapy of dizziness with several distinct etiologies.

SUMMARY

The present disclosure relates to compositions and methods forprophylaxis and/or therapy of dizziness in an individual. Inembodiments, the disclosure provides a pharmaceutical formulationcomprising lamotrigine and/or bupropion hydrochloride in atherapeutically effective amount for prophylaxis and/or therapy ofdizziness in an individual. In embodiments, the compositions compriseonly lamotrigine. Methods are provided for use in prophylaxis and/ortherapy of one or more symptoms of Meniere's Disease. In embodiments,the disclosure encompasses administering to an individual an individualdiagnosed with Meniere's Disease a composition comprising lamotriginesuch that dizziness associated with the Meniere's Disease is reduced, oris eliminated. In embodiments, lamotrigine is the only bioactivecompound in the composition. In embodiments, lamotrigine is the onlysodium channel blocking drug in the composition. In embodiments, thecomposition used to treat the individual does not comprise a diureticagent. In embodiments, the composition used to treat the individual doesnot comprise any of diazepam, lorazepam, promethazine, dimenhydrinate ormeclizine hydrochloride. Thus, the disclosure includes administering acomposition comprising lamotrigine to an individual with Meniere'sDisease such that dizziness is reduced or eliminated, and wherein thelamotrigine is the only drug the individual is taking that results inthe effect on dizziness is lamotrigine.

In one embodiment, the disclosure includes a pharmaceutical compositioncomprising lamotrigine packaged in a packaging material which comprisesprinted material on or in the packaging. The printed material includesan indication that the composition is for use in the treatment ofdizziness and/or vertigo. In an embodiment, the disclosure includes apharmaceutical composition comprising lamotrigine packaged in apackaging material and identified in print in or on the packagingmaterial that the composition is for use in the treatment of Meniere'sDisease. In embodiments, the packaging material includes informationrelated to a prescription for use of the pharmaceutical composition inthe prophylaxis and/or therapy of Meniere's Disease, and may includesuch information as dosage route, frequency and duration ofadministration.

In another aspect the disclosure include a kit comprising atherapeutically effective amount of lamotrigine, packaged in acontainer, the kit further comprising a label attached to or packagedwith the container, the label describing the contents of the containerand providing indications and/or instructions regarding use of thecontents of the container to treat dizziness and/or vertigo and/orMeniere's Disease.

In another aspect the disclosure includes an article of manufacturecomprising packaging material and lamotrigine provided in a separate orin a single pharmaceutical formulation in the packaging material,wherein the pharmaceutical composition is effective for the treatment ofa subject in need of prophylaxis or therapy for anti-dizziness/vertigo,and wherein the packaging material optionally comprises a label whichindicates that the lamotrigine can be used for at least ameliorating thesymptoms of Meniere's Disease and/or dizziness and/or vertigo.

DESCRIPTION OF THE FIGURES

FIG. 1: The graph indicates normal neuronal activity and presumed normaldizziness threshold. The solid wave line suggests the increased neuronalactivity in patients with migraine-associated vertigo.

FIG. 2: We propose that Lamotrigine may be able to suppress the neuronalhyperactivity and prevent the dizziness threshold from being reached,thus preventing dizziness and migraine.

FIG. 3: Patients with phobic postural vertigo may have pre-existing lowdizziness thresholds, which explains why patients are very sensitive tomotion, light, noise, stress, and, in severe situations, may experiencedizziness constantly.

FIG. 4: Anti-anxiety medications may be able to raise the dizzinessthreshold and treat the PPV dizziness.

FIG. 5: The graph demonstrates how dizziness patients can have both alow dizziness threshold and neuronal hyperactivity with a co-existingMAV and PPV diagnosis.

FIG. 6: The combination of Lamictal and WELLBUTRIN can suppress theneuronal hyperactivity and raise the dizziness threshold, which withoutintending to be constrained by theory, we believe achieved the optimaleffectiveness.

FIG. 7. Graph showing Improvement of Meniere's Vertigo Attacks withLamotrigine Treatment. The data show there were significantly fewervertigo attacks during the two lamotrigine treatment periods (3 monthsof titrtion period, 3 months of maintenance dosage) compared to the 3months prior to treatment (p<0.001, p<0.001). There were alsosignificantly fewer vertigo attacks during the 3 months afterlamotrigine maintenance relative to the 3 months of titration (p=0.04).

DETAILED DESCRIPTION

The present disclosure provides compositions and methods for prophylaxisand/or therapy of vertigo and/or dizziness. The vertigo and/or dizzinessfor which a prophylactic and/or therapeutic benefit is provided can bevertigo and/or dizziness in the absence of any associated neurologicaldisorder, or it can be associated with any of several disorders, orcombinations of such disorders, including but not necessarily limited toMeniere's Disease and Migraine-associated Vertigo (MAV).

In one aspect, the invention includes a method for prophylaxis and/ortherapy of Meniere's Disease. In general, the method comprisesadministering to an individual diagnosed with or suspected of havingMeniere's Disease a composition of the invention in an amount effectiveto prevent or lessen the severity of dizziness, or to reduce the numberof attacks, such as vertigo attacks, during a treatment period.

The terms “vertigo” and “dizziness” as used herein have art recognizedmeanings and can be readily diagnosed by the skilled artisan and includeimbalance and/or the sensation of the individual or the individual'senvironment spinning, moving to a non-horizontal plane, or that theindividual is about to fall. Likewise, diagnosis of Meniere's Diseaseand its symptoms, including but not necessarily limited to dizzinessassociated with it, can readily be performed by those skilled in theart.

In one embodiment, the disclosure includes a closed or sealed packagethat contains lamotrigine alone, or lamotrigine and bupropion in thesame or as separate pharmaceutical compositions. In embodiments, onlylamotrigine is included as an active drug in a closed or sealed packagethat has one or more closed or sealed vials, bottles, blister (bubble)packs, or any other suitable packaging for the sale, or distribution, oruse of pharmaceutical agents. In addition to the pharmaceuticalcompositions, the package may contain printed information. The printedinformation can be provided on a label, or on a paper insert, or printedon the packaging material itself. The printed information can includeinformation that identifies the lamotrigine, the amounts and types ofactive and inactive ingredients, an indication of what condition thepharmaceutical composition(s) is intended to treat, and instructions fortaking the pharmaceutical composition, such as the number of doses totake over a given period of time, and whether or not it should be takenwith certain types of foods or liquids. In one embodiment, the packagingand/or the pharmaceutical agents themselves is marked with the termLiveWell, or a variation of that term. Thus, in various embodiments theinvention includes: i) a pharmaceutical composition of the inventionpackaged in a packaging material and identified in print, or in or onthe packaging material, that the composition is for use in the treatmentof Meniere's Disease, or another disease or disorder that is has as asymptom dizziness/vertigo; ii) a kit comprising a therapeuticallyeffective amount of a composition of the invention, packaged in acontainer, the kit further comprising a label attached to or packagedwith the container, the label describing the contents of the containerand providing indications and/or instructions regarding use of thecontents of the container to treat Meniere's Disease, or another diseaseor disorder that is has as a symptom dizziness/vertigo; iii) apharmaceutical product comprising pharmaceutical packaging; and a solidformulation inside the packaging, wherein the formulation compriseslamotrigine, the product further comprising printed material withinstructions for using the product to treat Meniere's Disease, oranother disease or disorder that is has as a symptom dizziness/vertigo;iv) an article of manufacture comprising packaging material and at leastone pharmaceutical composition as described herein contained within thepackaging material, wherein the pharmaceutical composition is effectivefor the treatment of a subject in need of anti-dizziness/vertigoprophylaxis or therapy, and wherein the packaging material optionallycomprises a label which indicates that the pharmaceutical compositioncan be used for at least ameliorating the symptoms of Meniere's Disease,or another disease or disorder that is has as a symptomdizziness/vertigo. In certain embodiments, the printed information thatis part of the product and/or packaging relates to prophylaxis ortherapy of a condition that has as a symptom dizziness/vertigo, whereinthat condition is MAV or PPV.

Lamotrigine

Lamotrigine is marketed in the U.S. and Europe under the trade nameLAMICTAL. Lamotrigine has the chemical formula6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine. It has the molecularformula C₉H₇C₁₂N₅. It is designated by CAS Registry Number 84057-84-1which is incorporated herein by reference. It can have the molecularstructure:

LAMICTAL is commercially available in formulations for oraladministration in 25 mg, 100 mg, 150 mg and 200 mg doses. In addition tolamotrigine, these table can also comprise any of the followingcomponents: lactose; magnesium stearate; microcrystalline cellulose;povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100 mg tabletonly); ferric oxide, yellow (150 mg tablet only); and FD&C Blue No. 2Lake (200 mg tablet only), and combinations thereof.

LAMICTAL is also provided in the form of chewable dispersible tabletsfor oral administration. These tablets comprise 2 mg, 5 mg or 25 mglamotrigine. In addition to lamotrigine, these tablets can also compriseany of the following components: blackcurrant flavor, calcium carbonate,low-substituted hydroxypropyl cellulose, magnesium aluminum silicate,magnesium stearate, povidone, saccharin sodium, and sodium starchglycolate, and combinations thereof.

LAMICTAL is also provided in the form of orally disintegrating tabletsfor oral administration. These tablets comprise 25 mg, 50 mg, 100 mg, or200 mg lamotrigine. In addition to lamotrigine, these tablets can alsocomprise artificial any of the following components: cherry flavor,crospovidone, ethylcellulose, magnesium stearate, mannitol,polyethylene, and sucralose, and combinations thereof.

Bupropion

Bupropion (bupropion hydrochloride) is marketed under the tradenamesWELLBUTRIN, ZYBAN, VOXRA, BUDEPRION, PREXATON, ELONTRIL and APLENZIN. Ithas also been referred to in the art as amfebutamone. Bupropion has thechemical structure(±)-1-(3chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanonehydrochloride. The molecular formula is C₁₃H₁₈ClNO.HCl. It is designatedby CAS Registry Number CAS number 34841-39-9, which is incorporatedherein by reference. It can have the molecular structure:

A Bupropion formula marketed under the tradename WELLBUTRIN is suppliedfor oral administration as 75-mg and 100-mg film-coated tablets. Inaddition to bupropion hydrochloride, each tablet can comprise any of thefollowing components: 75-mg tablet—D&C Yellow No. 10 Lake, FD&C YellowNo. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystallinecellulose, polyethylene glycol, talc, and titanium dioxide; 100-mgtablet—FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, polyethyleneglycol, talc, and titanium dioxide, and combinations thereof.

A Bupropion formula marketed under the tradename WELLBUTRIN XL issupplied for oral administration as 150-mg and 300-mg extended-releasetablets. In addition to bupropion hydrochloride, the tablets cancomprise any of the following components: ethylcellulose aqueousdispersion, glyceryl behenate, methacrylic acid copolymer dispersion,polyvinyl alcohol, polyethylene glycol, povidone, silicon dioxide, andtriethyl citrate, and combinations thereof.

The compositions of the invention can include lamotrigine, bupropion,pharmaceutically acceptable salts thereof, and combinations thereof. Thecompositions of the invention are pharmaceutical compositions that canbe administered via any conventional route, including orally andintravenously. In certain embodiments, the compositions are administeredorally. In certain embodiments, a first composition comprisinglamotrigine can be administered. Optionally, a second, separatecomposition comprising bupropion can be administered. In certainembodiments, a first composition comprising bupropion can beadministered, and a second, separate composition comprising lamotriginecan be administered. Dosing schedules and amounts of the activeingredients modified on a case-by case basis by one skilled in the art,given the benefit of the present invention. In general, dosing will bedependent on the age, gender, size, and overall health of theindividual, whether or not any related neurological disorders arepresent, and the severity of the dizziness to be treated. In thisregard, the amounts of lamotrigine for any particular patient can betailored on a case by case basis in view of the present disclosure. Thecompositions of the invention can be formulated to provide controlledrelease of the ingredients, such that the ingredients can be releasedrapidly or slowly, as desirable.

The amount of lamotrigine dosage can be between 1.0 mg and 200.0 mg,inclusive, and inclusive of all integers there between to the firstdecimal point. In certain embodiments, the amount of lamotrigine in anindividual dose is 2 mg, 5 mg, 25 mg, 100 mg, 150 mg or 200 mg. Incertain embodiments, the dosage is 25 mg to 400 mg. The dosage can beadjusted as desired, such as by being increased in amounts of 25 mg at atime. The lamotrigine, whether administered alone or as part of combinedtreatment with Bupropion, can be administered, for example, once a dayor twice a day.

In embodiments, the individual treated according to the presentdisclosure is administered a composition comprising lamotrigine at leastonce a day. In embodiments, the composition is administered more thanonce a day, such as at least twice a day. In embodiments, thecomposition is administered between once and twice a day, or isadministered only once a day. In embodiment, lamotrigine is taken by theindividual in an amount between 10 mg to 500 mg, inclusive, andincluding all integers and ranges of integers there between. Inembodiments, between 25 mg to 200 mg of lamotrigine are administeredtwice daily (BID). In embodiments, the individual is treated for aninitial period of time with a first dosage, and then is treated with adifferent dosage for a second period of time. In embodiments, the firstperiod comprises a lower upper dosage than the second period. In oneembodiment, the first period is considered a titration period and thesecond period is considered a maintenance period.

In one non-limiting embodiment, the individual is treated with between25 mg to 200 mg BID for a period of between one and 4 weeks, inclusiveand including all ranges of days there between. In embodiments, thefirst period dosage is between 25 and 50 mg BID lamotrigine. Inembodiments, the individual is treated for the first period for a periodof between two weeks and three months at the first dosage, and istreated during a second period for another at least one, two, three, ormore months. The maintenance period can be extended indefinitely, andsubsequent rounds of titration and maintenance can be used depending ona variety of factors, such as whether or not the individual discontinuesthe treatment, and whether or not the MD-associated vertigo returns. Inembodiments, the maintenance period comprises treating the individualwith from 25 mg BID and 200 mg BID, inclusive and including all integersand ranges there between. In embodiments, the maintenance dosage is 100mg BID to 150 mg BID.

If Buproprion is also used, in certain embodiments, the amount ofBupropion in an individual dose can be between 50.0 mg and 450.0 mg,inclusive, and inclusive of all integers there between to the firstdecimal point. The dosage can be adjusted as desired, such as by beingincreased in amounts 75 mg to 450 mg. The dosage can be increased at,for example, increments of between 25 to 50 mg, and can be administeredonce or twice a day.

In certain embodiments, the invention is directed to prophylaxis and/ortherapy of dizziness for any individual who has been diagnosed with oris at risk for dizziness, whether or not the individual presents withone or more neurological disorders correlated with the dizziness. Incertain embodiments, the individual treated according to the method ofthe invention has not previously been diagnosed with, and/or has notbeen previously prescribed and/or treated with a composition of theinvention for any one, or any combination of the following conditions:migraine headaches; depression; anxiety; smoking cessation; seizures orconvulsions; epilepsy; bipolar disorder; peripheral neuropathy;trigeminal neuralgia; cluster headaches; neuropathic pain; a personalitydisorder; posttraumatic stress disorder; migraine-associated vertigo(MAV); phobic postural vertigo/chronic subjective dizziness (PPV/CSD);or selective serotonin reuptake inhibitor (SSRI)-induced sexualdysfunction. In embodiments, dizziness comprises vertigo.

Treatments according to the present invention can be carried out overvarious periods of time, during which the patients can be monitored forimprovements in dizziness symptoms.

In another embodiment, the invention provides a method for diagnosing anindividual as a candidate for dizziness/vertigo therapy. The methodcomprises testing an individual for dizziness and/or Meniere's Disease,and upon determining that the individual suffers from dizziness and/orMeniere's Disease, prescribing the individual therapy comprisingadministering to the individual a composition comprising Lamotrigine,Bupropion, or a combination thereof. In one embodiment, the methodfurther comprises administering the composition to the individual.

It will be recognized from the foregoing that the present invention isbased in part on our discovery that a commonly used anti-epilepticmedication and combinations of it with other compounds may be effectiveto treat or prevent Meniere's attacks, and to alleviate dizzinessassociated with other conditions. Results reflecting this are presentedin FIGS. 1-7 and support several aspects of approaching dizziness usingsingle and combined pharmaceutical approaches.

Many patients complain of a very different dizziness or imbalancesensation in between Meniere's attacks. These symptoms usually last fora shorter period of time, from seconds to minutes; are positionalmovement related, like bending or turning too fast; and can be relatedto exposure to light, noise and crowded environments. Unlike theMeniere's attacks, the dizziness is not associated with severe vertigo,nausea and vomiting and the symptoms usually resolve in seconds orminutes. We believe this secondary dizziness is more likely diagnosed asphobic postural vertigo (PPV) or chronic subjective dizziness (CSD). Webelieve the composition sold under the trade name Wellbutrin XL isparticularly well suited for the invention because it one of its majorside effects is a reduced seizure threshold, which could be neutralizedby combining it with Lamotrigine according to the invention, and thus,combination therapy using for Meniere's Patients using lamotrigen andbuproprion is an aspect of this disclosure.

Without intending to be constrained by any particular theory, we believethat Meniere's attacks may be like “migraine in the inner ear” generatedby unstable neuronal activity and this activity may be related to sodiumchannelopathy. So like anticonvulsants, Lamotrigine may either stop thegeneration of Meniere's attacks or prevent the propagation of Meniere'sattacks from the ear to the central nervous system. Furthermore,Wellbutrin XL, as a norepinephrine reuptake inhibitor, may be raisingdopamine levels in the brain and raising the threshold for neuronalactivity, consequently preventing the generation of phobic posturalvertigo or chronic subjective dizziness. Therefore, we believe thatLamotrigine may be able to stop the Meniere's attacks and Wellbutrin XLmay be able to help the secondary phobic postural vertigo and underlyinganxiety. Thus, in addition to the prophylactic and therapeuticapproaches to treating dizziness, it is contemplated that thecombination of Lamotrigine and Wellbutrin could be an effectivetreatment for Meniere's disease and may prevent permanent damage to thevestibular (imbalance and vertigo) and cochlear (hearing loss)functions, and also significantly improve the quality of the patient'slife.

With respect to MAV, and again without wishing to be bound by anyparticular theory, we believe that a combination of Lamotrigine andWellbutrin XL will send MAV disorders into remission. This is based onthe idea that migraine-associated vertigo is a central phenomenon inwhich neuron activity is hyperactive and surpasses a dizziness thresholdduring the attacks. This neuron hyperactivity in the brain is similar tothe activity seen in seizure patients and could be treated in acomparable manner. Anti-epileptics have successfully served as migraineprophylactic medications by mitigating neuron activity. However,FDA-approved Topiramate has several unwanted side effects, includingconfusion, slowed thinking, memory problems, trouble concentrating andkidney stones. Lamotrigine and Topiramate both act as anti-epilepticsodium channel blockers, but Lamotrigine has fewer risks and sideeffects. Accordingly, we propose that Lamotrigine will reduce the neuronactivity and prevent the dizziness threshold from being reached withoutunwanted mental and physical reactions. Moreover, Wellbutrin XL willlikely function as an effective supplemental anti-anxiety medication.Although tricyclic antidepressants were ranked low for relief of eithermigraine or vestibular symptoms, Wellbutrin XL is a non-tricyclicantidepressant and still has the potential for relief.^(xxiii) Evidencepresented here as described further below shows that a pharmacotherapycomprising Lamotrigine and Wellbutrin XL could be an effective approachto treat the symptoms of a large population suffering from otherwiseuntreated dizziness problems. See FIGS. 1 and 2.

With respect to Phobic Postural Vertigo, both Meniere's disease andmigraine-associated vertigo can have persisting dizziness even after theprimary symptoms are treated. The residual imbalance can be from thevestibular disorder exacerbating previous anxiety conditions or from thenew additional stress and anxiety of having the primary vestibulardisorder. These psychological effects can be so great that they manifestinto a secondary problem termed phobic postural vertigo (PPV). Holmberet al. describes PPV as “(i) dizziness and subjective disturbance ofbalance while standing or walking, despite normal clinical balancetests, (ii) fluctuating unsteadiness for seconds to minutes, ormomentary perceptions of illusory body perturbations, (iii) usually aperceptual stimulus or social situation as a provoking factor with atendency towards rapid conditioning, generalization and avoidancebehavior, (iv) anxiety and vegetative symptoms during or after vertigo,(v) an obsessive-compulsive type personality, labile affect or milddepression and (vi) onset frequently after a period of emotional stress,a serious illness or a vestibular disorder”.^(xxiv) Although physicalsymptoms of the disorder fluctuate and can decrease in severity overtime, complete recoveries are rarely made.^(xxv) Research on cognitivebehavioral therapy has shown only a limited long-term improvement forPPV patients, leaving many individuals to continue experiencingdebilitating symptoms.^(xxvi) The problem may not be in ineffectivetreatments, but in solutions that only address limited aspects of thedisorder. Recently Staab et al. proposed the new term chronic subjectivedizziness (CSD) to replace phobic postural vertigo. The primarycriterion change lies in chronic subjective dizziness diagnosesrequiring symptoms to exist for three months or more. More research onthe treatment of PPV/CSD has been reported, mostly anti-anxietymedications^(xxvii).

PPV is often observed in patients who are also diagnosed withmigraine-associated vertigo; PPV has been observed in up to 30% of MAVpatients during one study.^(xxviii) Our own research has shown that PPVand MAV present non-statistically different clinical results duringoptokinetic (OPK) drum and rotary chair testing. Both groups of patientshave dizziness complaints after OPK drum stimulation and showed eitherhigh gain or low gain patterns in the higher frequencies on the rotarychair testing.^(xxix) This co-occurrence provides the possibility thatthese patients have both a lower dizziness threshold as well as theneuronal hyperactivity exhibited in phobic postural vertigo andmigraine-associated vertigo patients, respectively. Therefore, the bestmanagement would include pharmaceutical treatment for both conditions,and for reasons stated above, the Lamotrigine-Wellbutrin XL combinationwould be a potential candidate for successful pharmacotherapy. Ourresearch showed that antidepressants or anti-anxiety medications workwell for patients with PPV/CSD. However, a combination of theLamotrigine-Wellbutrin XL medications for this group of patients has hadmuch more success. See FIGS. 3, 4, 5 and 6 and the description ofresults below.

It will be apparent to those skilled in the art from and the presentdescription and Figures that the combination medication of Lamotrigineand Wellbutrin XL, as well as Lamotrigine alone, is likely able to raisedizziness thresholds and decrease the neuronal activity at the sametime. Accordingly, we propose that the approaches disclosed hereinshould have greater efficacy for both types of dizziness/vertigo.Further, the combination of Lamotrigine and Wellbutrin may not only beeffective for Meniere's disease, but also for patients withmigraine-associated vertigo and phobic postural vertigo/chronicsubjective dizziness. All three patient groups combined constitutealmost two-thirds of the total dizziness population. Dizziness continuesto be one of the most common clinical presentations; it is listed as thethird most common reason for a doctor visit for those 60 years old orolder and becomes the number one reason for a doctor visit for thoseover the age of 70. The neuronal “threshold” theory may be able toexpand to other episodic neurologic or psychiatric disorders: likemigraine, bipolar disorders, anxiety/panic or unexplained episodicneurologic spells. Neuronal hyperactivity happens in different parts ofthe brain and could then manifest as different symptoms. Therefore, webelieve that the compositions and methods of the invention may be usefulfor a wide range of clinical applications for other episodic neurologicand psychiatric disorders in addition to the treatment ofdizziness/vertigo.

Example 1

This Example provides a description of experiments and resultssupporting the use of lamotrigine alone for prophylaxis and/or therapyif dizziness in MD patients.

Standard protocol approvals, registrations and patient consents. TheState University of New York at Buffalo IRB approved this study.

Population. A retrospective and prospective review was performed onpatients who were older than 18 years old, diagnosed with activedefinite MD at the Dent Dizziness, Balance and Tinnitus Center andtreated with lamotrigine. Definite MD is defined as two or more episodesof vertigo that last for ≥20 minutes with documented hearing loss on atleast one occasion, tinnitus and/or aural fullness, and other causesexcluded. Active MD status requires patients to experience at leastthree vertigo attacks during the three months prior to treatment.

Clinical data. Data collected included demographic information, historyof MD, prior medical treatment, clinical diagnosis, clinicalpresentation, stage of the disease, and frequency of Meniere's vertigoattacks prior to and after treatment. The staging of MD was based on thefour-tone average of the pure-tone thresholds at 0.5, 1, 2 and 3 kHz ofthe worst audiogram during the six months before treatment. Thequestionnaires used were the Dizziness Handicap Inventory (DHI) and theCenter's Dizziness Questionnaire. Current or past history ofanxiety/depression, migraine problems, and use of anti-anxietymedication were also analyzed.

Outcome variable. The primary outcome measure was the reduction ofMeniere's vertigo attacks at both three months after lamotrigineinitiation (primarily the titration period) and three months aftertreatment at maintenance dosage. Secondary outcome measures included DHIscores and patient reports of clinical improvement. Data were confirmedby review of physicians' notes, vestibular and audiogram testingresults, and supporting data. Means and standard deviations (SDs) werecalculated for all continuous variables and proportions for allcategorical variables. The primary research questions were whether ornot lamotrigine led to a reduction of Ménière's vertigo attacks andwhether or not lamotrigine led to improvement in quality of life for MDpatients.

Statistical analysis. The overall difference in Meniere's vertigoattacks among 3 months pre-treatment, 3 months of titration, and 3months of maintenance treatment was evaluated by Friedman's test, whichis a nonparametric test for treatment differences in a randomizedcomplete block design. The Wilcoxon signed rank sum test, which is thenonparametric version of a paired sample t-test, was used for thepairwise comparisons of Meniere's vertigo attacks from the threedifferent time periods as well as DHI before and after treatment.Fisher's exact test was used to evaluate whether treatment effectivenesswas affected by migraine or anxiety comorbidities. For all of thesestatistical tests, the tests were two-sided, and the level ofsignificance was set to 0.05. Differences were considered significant ifthe p-value was less than 0.05.

The following results were obtained.

Clinical characteristics. 45 patients matched the criteria for thestudy, which are the following: diagnosis of active definite MD andprescription of lamotrigine. The mean age of the patient cohort was 61years (SD 16.5). In terms of sex and race, 29 patients were female and42 were Caucasian. There were 33 patients who had a history ofanxiety/depression (73%), with 22 patients on anti-anxiety medication(49%), and 22 patients had a history of migraine (49%).

Based on the four-tone average, 7 patients were diagnosed with stage one(≤ to 25 dB), 10 with stage two (between 26 and 40 dB), 19 with stagethree (between 41 and 70 dB), and eight with stage four (>70 dB). Therewas one patient who did not have an audio report. The mean priortreatment DHI score was 47.6 (SD 19.6). The mean number of vertigoattacks during the three months prior to treatment was 12.7 (SD 11.6).

Lamotrigine titration. All 45 patients began a titration of lamotrigineof 25 mg BID for two weeks to 50 mg BID for two weeks. Final maintenancedosages varied between 25 mg BID and 200 mg BID due to individualpatient tolerance and response; 29 patients were on either 100 mg BID or150 mg BID maintenance dosages (64%). There was one patient who was lostto follow-up. There were four patients who discontinued lamotrigine dueto side effects: one experienced stomachaches and diarrhea, onecomplained of hallucinations, and two developed rashes.

Outcome after lamotrigine treatment. Out of all 45 study patients, 38(84%) reported an improvement in Ménière's vertigo attacks withlamotrigine treatment. The mean number of vertigo attacks three monthsafter initiation (primarily the titration period) was 4.5 (SD 6.2) andthe mean number after three months of maintenance dosage was 1.9 (SD4.6). There were significantly fewer vertigo attacks during these twotreatment periods than the period prior to treatment (p<0.001, p<0.001;FIG. 7). There were also significantly fewer vertigo attacks during the3 months of lamotrigine maintenance relative to the 3 months oftitration (p=0.04; FIG. 7), indicating the dose effect of lamotrigine.More than half of the improved patients (21 of 38) had a completeresolution of their Ménière's vertigo attacks during the three monthmaintenance period. The mean post-treatment DHI score was 28.6 (SD20.9). On average, the post-DHI score was 19 points less than thepre-DHI score; this difference was statistically significant (p=0.001).

Among the patients who reported improvement, there were 20 who hadmigraine and 28 with anxiety/depression disorder. However, vertigoattack reduction and remission were not affected by migraine (p=0.414)nor anxiety/depression (p=1.000) comorbidities (Table 1). These datareinforce the notion that lamotrigine was effective at treatingMeniere's disease and not the comorbidities of the disease.

TABLE 1 Effectiveness of Lamotrigine for Meniere's vertigo attacks wasnot affected by the diagnosis of Migraine or Anxiety MD with migraine MDwithout migraine (anxiety) (anxiety) Total Vertigo attack free 11 (15)10 (6)  21 Vertigo reduced  9 (13) 8 (4) 17 Vertigo unchanged 1 (1) 1(1) 2 Side effect 1 (3) 3 (1) 4 Lost to follow-up 0 (1) 1 (0) 1Vertigo attack reduction and remission were not affected by migraine(p=0.414) nor anxiety/depression (p=1.000) comorbidities.

While the invention has been described through specific embodiments,routine modifications will be apparent to those skilled in the art andsuch modifications are intended to be within the scope of the presentinvention.

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We claim:
 1. A method comprising administering to an individualdiagnosed with Meniere's Disease a pharmaceutical composition comprisingan effective amount of lamotrigine or a pharmaceutically acceptable saltthereof such that the effective amount of the lamotrigine or thepharmaceutically acceptable salt thereof is sufficient to reducedizziness that is caused by the Meniere's Disease in the individual,wherein the lamotrigine or the pharmaceutically acceptable salt thereofis the only bioactive compound in the pharmaceutical composition that iseffective to treat the dizziness caused by the Meniere's Disease,wherein the individual is also diagnosed with phobic postural vertigoand/or chronic subjective dizziness, the method further comprisingadministering to the individual a pharmaceutical composition comprisingan effective amount of bupropion or a pharmaceutically acceptable saltthereof such that the phobic postural vertigo and/or chronic subjectivedizziness is also reduced.
 2. The method of claim 1, wherein theindividual is diagnosed with the phobic postural vertigo.
 3. The methodof claim 1, wherein the individual is diagnosed with the chronicsubjective dizziness.
 4. The method of claim 1, wherein the effectiveamount of lamotrigine comprises 25 mg to 400 mg.
 5. The method of claim1, wherein the effective amount of bupropion or the pharmaceuticallyacceptable salt thereof is 150 mg to 300 mg.
 6. The method of claim 2,wherein the effective amount of bupropion or the pharmaceuticallyacceptable salt thereof is 150 mg to 300 mg.
 7. The method of claim 3,wherein the effective amount of bupropion or the pharmaceuticallyacceptable salt thereof is 150 mg to 300 mg.
 8. The method of claim 4,wherein the effective amount of bupropion or the pharmaceuticallyacceptable salt thereof is 150 mg to 300 mg.